Inhomogeneous Magnetization Transfer (ihMT) imaging in the acute cuprizone mouse model of demyelination/remyelination.

BACKGROUND: To investigate the association of ihMT (inhom signals with the demyelination and remyelination phases of the acute cuprizone mouse model in comparison with histology, and to assess the extent of tissue damage and repair from MRI data. METHODS: Acute demyelination by feeding 0.2% cuprizone for five weeks, followed by a four-week remyelination period was applied on genetically modified plp-GFP mice. Animals were scanned at different time points of the demyelination and remyelination phases of the cuprizone model using a multimodal MRI protocol, including ihMT T1D-filters, MPF (Macromolecular Proton Fraction) and R1 (longitudinal relaxation rate). For histology, plp-GFP (proteolipid protein - Green Fluorescent Protein) microscopy and LFB (Luxol Fast Blue) staining were employed as references for the myelin content. Comparison of MRI with histology was performed in the medial corpus callosum (mCC) and cerebral cortex (CTX) at two brain levels whereas ROI-wise and voxel-based analyses of the MRI metrics allowed investigating in vivo the spatial extent of myelin alterations. RESULTS: IhMT high-pass T1D-filters, targeted toward long T1D components, showed significant temporal variations in the mCC consistent with the effects induced by the cuprizone toxin. In addition, the corresponding signals correlated strongly and significantly with the myelin content assessed by GFP fluorescence and LFB staining over the demyelination and the remyelination phases. The signal of the band-pass T1D-filter, which isolates short T1D components, showed changes over time that were poorly correlated with histology, hence suggesting a sensitivity to pathological processes possibly not related to myelin. Although MPF was also highly correlated to histology, ihMT high-pass T1D-filters showed better capability to characterize the spatial-temporal patterns during the demyelination and remyelination phases of the acute cuprizone model (e.g., rostro-caudal gradient of demyelination in the mCC previously described in the literature). CONCLUSIONS: IhMT sequences selective for long T1D components are specific and sensitive in vivo markers of demyelination and remyelination and have successfully captured the spatially heterogeneous pattern of the demyelination and remyelination mechanisms in the cuprizone model. Interestingly, differences in signal variations between the ihMT high-pass and band-pass T1D-filter, suggest a sensitivity of the ihMT sequences targeted to short T1Ds to alterations other than those of myelin. Future studies will need to further address these differences by examining more closely the origin of the short T1D components and the variation of each T1D component in pathology.

Fast-spin-echo versus rapid gradient-echo for 3D magnetization-prepared acquisitions: Application to inhomogeneous magnetization transfer.

PURPOSE: To evaluate the benefits of fast spin echo (FSE) imaging over rapid gradient-echo (RAGE) for magnetization-prepared inhomogeneous magnetization transfer (ihMT) imaging. METHODS: A 3D FSE sequence was modified to include an ihMT preparation (ihMT-FSE) with an optional CSF suppression based on an inversion-recovery (ihMT-FLAIR). After numeric simulations assessing SNR benefits of FSE and the potential impact of an additional inversion-recovery, ihMT-RAGE, ihMT-FSE, and ihMT-FLAIR sequences were compared in a group of six healthy volunteers, evaluating image quality, thermal, and physiological noise as well as quantification using an ihMT saturation (ihMTsat) approach. A preliminary exploration in the cervical spinal cord was also conducted in a group of three healthy volunteers. RESULTS: Several fold improvements in thermal SNR were observed with ihMT-FSE in agreement with numerical simulations. However, we observed significantly higher physiological noise in ihMT-FSE compared to ihMT-RAGE that was mitigated in ihMT-FLAIR, which provided the best total SNR (+74% and +49% compared to ihMT-RAGE in the white and gray matter, P ≤ 0.004). IhMTsat quantification was successful in all cases with strong correlation between all sequences (r2 > 0.75). Early experiments showed potential for spinal cord imaging. CONCLUSIONS: FSE generally offers higher SNR compared to gradient-echo based acquisitions for magnetization-prepared contrasts as illustrated here in the case of ihMT. However, physiological noise has a significant effect, but an inversion-recovery-based CSF suppression was shown to be efficient in mitigating effects of CSF motion.

Quantitative magnetization transfer MRI unbiased by on-resonance saturation and dipolar order contributions.

PURPOSE: To demonstrate the bias in quantitative MT (qMT) measures introduced by the presence of dipolar order and on-resonance saturation (ONRS) effects using magnetization transfer (MT) spoiled gradient-recalled (SPGR) acquisitions, and propose changes to the acquisition and analysis strategies to remove these biases. METHODS: The proposed framework consists of SPGR sequences prepared with simultaneous dual-offset frequency-saturation pulses to cancel out dipolar order and associated relaxation (T1D ) effects in Z-spectrum acquisitions, and a matched quantitative MT (qMT) mathematical model that includes ONRS effects of readout pulses. Variable flip angle and MT data were fitted jointly to simultaneously estimate qMT parameters (macromolecular proton fraction [MPF], T2,f , T2,b , R, and free pool T1 ). This framework is compared with standard qMT and investigated in terms of reproducibility, and then further developed to follow a joint single-point qMT methodology for combined estimation of MPF and T1 . RESULTS: Bland-Altman analyses demonstrated a systematic underestimation of MPF (-2.5% and -1.3%, on average, in white and gray matter, respectively) and overestimation of T1 (47.1 ms and 38.6 ms, on average, in white and gray matter, respectively) if both ONRS and dipolar order effects are ignored. Reproducibility of the proposed framework is excellent (ΔMPF = -0.03% and ΔT1 = -19.0 ms). The single-point methodology yielded consistent MPF and T1 values with respective maximum relative average bias of -0.15% and -3.5 ms found in white matter. CONCLUSION: The influence of acquisition strategy and matched mathematical model with regard to ONRS and dipolar order effects in qMT-SPGR frameworks has been investigated. The proposed framework holds promise for improved accuracy with reproducibility.

Inhomogeneous magnetization transfer imaging: Concepts and directions for further development.

Off-resonance radio frequency irradiation can induce the ordering of proton spins in the dipolar fields of their neighbors, in molecules with restricted mobility. This dipolar order decays with a characteristic relaxation time, T1D , that is very different from the T1 and T2 relaxation of the nuclear alignment with the main magnetic field. Inhomogeneous magnetization transfer (ihMT) imaging is a refinement of magnetization transfer (MT) imaging that isolates the MT signal dependence on dipolar order relaxation times within motion-constrained molecules. Because T1D relaxation is a unique contrast mechanism, ihMT may enable improved characterization of tissue. Initial work has stressed the high correlation between ihMT signal and myelin density. Dipolar order relaxation appears to be much longer in membrane lipids than other molecules. Recent work has shown, however, that ihMT acquisitions may also be adjusted to emphasize different ranges of T1D . These newer approaches may be sensitive to other microstructural components of tissue. Here, we review the concepts and history of ihMT and outline the requirements for further development to realize its full potential.

Automatic segmentation of deep grey nuclei using a high-resolution 7T magnetic resonance imaging atlas-Quantification of T1 values in healthy volunteers.

We present a new consensus atlas of deep grey nuclei obtained by shape-based averaging of manual segmentation of two experienced neuroradiologists and optimized from 7T MP2RAGE images acquired at (.6 mm)3 in 60 healthy subjects. A group-wise normalization method was used to build a high-contrast and high-resolution T1 -weighted brain template (.5 mm)3 using data from 30 out of the 60 controls. Delineation of 24 deep grey nuclei per hemisphere, including the claustrum and 12 thalamic nuclei, was then performed by two expert neuroradiologists and reviewed by a third neuroradiologist according to tissue contrast and external references based on the Morel atlas. Corresponding deep grey matter structures were also extracted from the Morel and CIT168 atlases. The data-derived, Morel and CIT168 atlases were all applied at the individual level using non-linear registration to fit the subject reference and to extract absolute mean quantitative T1 values derived from the 3D-MP2RAGE volumes, after correction for residual B1+ biases. Three metrics (the Dice and the volumetric similarity coefficients and a novel Hausdorff distance) were used to estimate the inter-rater agreement of manual MRI segmentation and inter-atlas variability, and these metrics were measured to quantify biases due to image registration, and their impact on the measurements of the quantitative T1 values was highlighted. This represents a fully automated segmentation process permitting the extraction of unbiased normative T1 values in a population of young healthy controls as a reference for characterizing subtle structural alterations of deep grey nuclei relevant to a range of neurological diseases.

A strategy to reduce the sensitivity of inhomogeneous magnetization transfer (ihMT) imaging to radiofrequency transmit field variations at 3 T.

PURPOSE: To minimize the sensitivity of inhomogeneous magnetization transfer gradient-echo (ihMT-GRE) imaging to radiofrequency (RF) transmit field ( B1+ ) inhomogeneities at 3 T. METHODS: The ihMT-GRE sequence was optimized by varying the concentration of the RF saturation energy over time, obtained by increasing the saturation pulse power while extending the sequence repetition time (TR). Different protocols were tested using numerical simulations and human in vivo experiments in the brain white matter (WM) of healthy subjects at 3 T. The sensitivity of the ihMT ratio (ihMTR) to B1+ variations was investigated by comparing measurements obtained at nominal transmitter adjustments and following a 20% global B1+ drop. The resulting relative variations (δihMTR ) were evaluated voxelwise as a function of the local B1+ distribution. The reproducibility of the protocol providing minimal B1+ bias was assessed in a test-retest experiment. RESULTS: In line with simulations, ihMT-GRE experiments conducted at high concentration of the RF energy over time demonstrated strong reduction of the B1+ inhomogeneity effects in the human WM. Under the optimal conditions of 350-ms TR and 3-µT root mean square (RMS) saturation power, 73% of all WM voxels presented δihMTR below 10%. Reproducibility analysis yielded a close-to-zero systematic bias (ΔihMTR = -0.081%) and a high correlation (ρ² = 0.977) between test and retest experiments. CONCLUSION: Concentrating RF saturation energy in ihMT-GRE sequences mitigates the sensitivity of the ihMTR to B1+ variations and allows for clinical-ready ihMT imaging at 3 T. This feature is of particular interest for high and ultra-high field applications.

T1D -weighted ihMT imaging - Part I. Isolation of long- and short-T1D components by T1D -filtering.

PURPOSE: To identify T1D -filtering methods, which can specifically isolate various ranges of T1D components as they may be sensitive to different microstructural properties. METHODS: Modified Bloch-Provotorov equations describing a bi-T1D component biophysical model were used to simulate the inhomogeneous magnetization transfer (ihMT) signal from ihMTRAGE sequences at high RF power and low duty-cycle with different switching time values for the dual saturation experiment: Δt = 0.0, 0.8, 1.6, and 3.2 ms. Simulations were compared with experimental signals on the brain gray and white matter tissues of healthy mice at 7T. RESULTS: The lengthening of Δt created ihMT high-pass T1D -filters, which efficiently eliminated the signal from T1D components shorter than 1 ms, while partially attenuating that of longer components (≥ 1 ms). Subtraction of ihMTR images obtained with Δt = 0.0 ms and Δt = 0.8 ms generated a new ihMT band-pass T1D -filter isolating short-T1D components in the 100-µs to 1-ms range. Simulated ihMTR values in central nervous system tissues were confirmed experimentally. CONCLUSION: Long- and short-T1D components were successfully isolated with high RF power and low duty-cycle ihMT filters in the healthy mouse brain. Future studies should investigate the various T1D -range microstructural correlations in in vivo tissues.

T1D -weighted ihMT imaging - Part II. Investigating the long- and short-T1D components correlation with myelin content. Comparison with R1 and the macromolecular proton fraction.

PURPOSE: To investigate the long- and short-T1D components correlation with myelin content using inhomogeneous magnetization transfer (ihMT) high-pass and band-pass T1D -filters and to compare ihMT, R1 , and the macromolecular proton fraction (MPF) for myelin specific imaging. METHODS: The 3D ihMT rapid gradient echo (ihMTRAGE) sequences with increasing switching times (Δt) were used to derive ihMT high-pass T1D -filters with increasing T1D cutoff values and an ihMT band-pass T1D -filter for components in the 100 µs to 1 ms range. 3D spoiled gradient echo quantitative MT (SPGR-qMT) protocols were used to derive R1 and MPF maps. The specificity of R1 , MPF, and ihMT T1D -filters was evaluated by comparison with two histological reference techniques for myelin imaging. RESULTS: The higher contribution of long-T1D s as compared to the short components as Δt got longer led to an increase in the specificity to myelination. In contrast, focusing on the signal originating from a narrow range of short-T1D s (< 1 ms) as isolated by the band-pass T1D -filter led to lower specificity. In addition, the significantly lower r2 correlation coefficient of the band-pass T1D -filter suggests that the origin of short-T1D components is mostly associated with non-myelin protons. Also, the important contribution of short-T1D s to the estimated MPF, explains its low specificity to myelination as compared to the ihMT high-pass T1D -filters. CONCLUSION: Long-T1D components imaging by means of ihMT high-pass T1D -filters is proposed as an MRI biomarker for myelin content. Future studies should enable the investigation of the sensitivity of ihMT T1D -filters for demyelinating processes.

Three-dimensional inhomogeneous magnetization transfer with rapid gradient-echo (3D ihMTRAGE) imaging.

PURPOSE: To demonstrate the feasibility of integrating the magnetization transfer (MT) preparations required for inhomogeneous MT (ihMT) within an MPRAGE-style acquisition. Such a sequence allows for reduced power deposition and easy inclusion of other modules. METHODS: An ihMT MPRAGE-style sequence (ihMTRAGE) was initially simulated to investigate acquisition of the 3D ihMT data sequentially, or in an interleaved manner. The ihMTRAGE sequence was implemented on a 3T clinical scanner to acquire ihMT data from the brain and spine. RESULTS: Both simulations and in vivo data provided an ihMT signal that was significantly greater using a sequential ihMTRAGE acquisition, compared with an interleaved implementation. Comparison with a steady-state ihMT acquisition (defined as having one MT RF pulse between successive acquisition modules) demonstrated how ihMTRAGE allows for a reduction in average power deposition, or greater ihMT signal at equal average power deposition. Inclusion of a prospective motion-correction module did not significantly affect the ihMT signal obtained from regions of interest in the brain. The ihMTRAGE acquisition allowed combination with a spatial saturation module to reduce phase wrap artifacts in a cervical spinal cord acquisition. CONCLUSIONS: Use of preparations necessary for ihMT experiments within an MPRAGE-style sequence provides a useful alternative for acquiring 3D ihMT data. Compared with our steady-state implementation, ihMTRAGE provided reduced power deposition, while allowing use of the maximum intensity from off-resonance RF pulses. The 3D ihMTRAGE acquisition allowed combination of other modules with the preparation necessary for ihMT experiments, specifically motion compensation and spatial saturation modules.

Whole brain inhomogeneous magnetization transfer (ihMT) imaging: Sensitivity enhancement within a steady-state gradient echo sequence.

PURPOSE: To implement, characterize, and optimize an interleaved inhomogeneous magnetization transfer (ihMT) gradient echo sequence allowing for whole-brain imaging within a clinically compatible scan time. THEORY AND METHODS: A general framework for ihMT modelling was developed based on the Provotorov theory of radiofrequency saturation, which accounts for the dipolar order underpinning the ihMT effect. Experimental studies and numerical simulations were performed to characterize and optimize the ihMT-gradient echo dependency with sequence timings, saturation power, and offset frequency. The protocol was optimized in terms of maximum signal intensity and the reproducibility assessed for a nominal resolution of 1.5 mm isotropic. All experiments were performed on healthy volunteers at 1.5T. RESULTS: An important mechanism driving signal optimization and leading to strong ihMT signal enhancement that relies on the dynamics of radiofrequency energy deposition has been identified. By taking advantage of the delay allowed for readout between ihMT pulse bursts, it was possible to boost the ihMT signal by almost 2-fold compared to previous implementation. Reproducibility of the optimal protocol was very good, with an intra-individual error < 2%. CONCLUSION: The proposed sensitivity-boosted and time-efficient steady-state ihMT-gradient echo sequence, implemented and optimized at 1.5T, allowed robust high-resolution 3D ihMT imaging of the whole brain within a clinically compatible scan time. Magn Reson Med 79:2607-2619, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

In vivo measurement of a new source of contrast, the dipolar relaxation time, T1D , using a modified inhomogeneous magnetization transfer (ihMT) sequence.

PURPOSE: This paper describes a technique that can be used in vivo to measure the dipolar relaxation time, T1D , of macromolecular protons contributing to magnetization transfer (MT) in tissues and to produce quantitative T1D maps. THEORY AND METHODS: The technique builds upon the inhomogeneous MT (ihMT) technique that is particularly sensitive to tissue components with long T1D . A standard ihMT experiment was altered to introduce a variable time for switching between positive and negative offset frequencies for RF saturation. A model for the dependence of ihMT was developed and used to fit data acquired in vivo. RESULTS: Application of the method to images from brains of healthy volunteers produced values of T1D = (5.9 ± 1.2) ms in gray matter and T1D = (6.2 ± 0.4) ms in white matter regions and provided maps of the T1D parameter. CONCLUSION: The model and experiments described provide access to a new relaxation characteristic of tissue with potentially unique diagnostic information. Magn Reson Med 78:1362-1372, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Magnetization transfer from inhomogeneously broadened lines (ihMT): Improved imaging strategy for spinal cord applications.

PURPOSE: Inhomogeneous magnetization transfer (ihMT) shows great promise for specific imaging of myelinated tissues. Whereas the ihMT technique has been previously applied in brain applications, the current report presents a strategy for cervical spinal cord (SC) imaging free of cerebrospinal fluid (CSF) pulsatility artifacts. METHODS: A pulsed ihMT preparation was combined with a single-shot HASTE readout. Electrocardiogram (ECG) synchronization was used to acquire all images during the quiescent phase of SC motion. However ihMT signal quantification errors may occur when a variable recovery delay is introduced in the sequence as a consequence of variable cardiac cycle. A semiautomatic retrospective correction algorithm, based on repetition time (TR) -matching, is proposed to correct for signal variations of long T1 -components (e.g., CSF). RESULTS: The proposed strategy combining ECG synchronization and retrospective data pairing led to clean SC images free of CSF artifacts. Lower variability of the ihMT metrics were obtained with the correction algorithm, and allowed for shorter TR to be used, hence improving signal-to-noise ratio efficiency. CONCLUSION: The proposed methodology enabled faster acquisitions, while offering robust ihMT quantification and exquisite SC image quality. This opens great perspectives for widening the in vivo characterization of SC physiopathology using MRI, such as studying white matter tracts microstructure or impairment in degenerative pathologies. Magn Reson Med 77:581-591, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Region-specific impairment of the cervical spinal cord (SC) in amyotrophic lateral sclerosis: A preliminary study using SC templates and quantitative MRI (diffusion tensor imaging/inhomogeneous magnetization transfer).

In this preliminary study, our objective was to investigate the potential of high-resolution anatomical imaging, diffusion tensor imaging (DTI) and conventional/inhomogeneous magnetization transfer imaging [magnetization transfer (MT)/inhomogeneous magnetization transfer (ihMT)] at 3 T, analyzed with template-extracted regions of interest, to measure the atrophy and structural changes of white (WM) and gray (GM) matter spinal cord (SC) occurring in patients with amyotrophic lateral sclerosis (ALS). Ten patients with ALS and 20 age-matched healthy controls were recruited. SC GM and WM areas were automatically segmented using dedicated templates. Atrophy indices were evaluated from T2 *-weighted images at each vertebral level from cervical C1 to C6. DTI and ihMT metrics were quantified within the corticospinal tract (CST), posterior sensory tract (PST) and anterior GM (aGM) horns at the C2 and C5 levels. Clinical disabilities of patients with ALS were evaluated using the Revised ALS Functional Rating Scale, upper motor neuron (UMN) and Medical Research Council scorings, and correlated with MR metrics. Compared with healthy controls, GM and WM atrophy was observed in patients with ALS, especially at lower cervical levels, where a strong correlation was also observed between GM atrophy and the UMN score (R = -0.75, p = 0.05 at C6). Interestingly, a significant decrease in ihMT ratio was found in all regions of interest (p < 0.0008), fractional anisotropy (FA) and MT ratios decreased significantly in CST, especially at C5 (p < 0.005), and λ// (axial diffusivity) decreased significantly in CST (p = 0.0004) and PST (p = 0.003) at C2. Strong correlations between MRI metrics and clinical scores were also found (0.47 < |R| < 0.87, p < 0.05). Altogether, these preliminary results suggest that high-resolution anatomical imaging and ihMT imaging, in addition to DTI, are valuable for the characterization of SC tissue impairment in ALS. In this study, in addition to an important SC WM demyelination, we also observed, for the first time in ALS, impairments of cervical aGM.

Tract-specific and age-related variations of the spinal cord microstructure: a multi-parametric MRI study using diffusion tensor imaging (DTI) and inhomogeneous magnetization transfer (ihMT).

Being able to finely characterize the spinal cord (SC) microstructure and its alterations is a key point when investigating neural damage mechanisms encountered in different central nervous system (CNS) pathologies, such as multiple sclerosis, amyotrophic lateral sclerosis or myelopathy. Based on novel methods, including inhomogeneous magnetization transfer (ihMT) and dedicated SC probabilistic atlas post-processing, the present study focuses on the in vivo characterization of the healthy SC tissue in terms of regional microstructure differences between (i) upper and lower cervical vertebral levels and (ii) sensory and motor tracts, as well as differences attributed to normal aging. Forty-eight healthy volunteers aged from 20 to 70 years old were included in the study and scanned at 3 T using axial high-resolution T2 *-w imaging, diffusion tensor imaging (DTI) and ihMT, at two vertebral levels (C2 and C5). A processing pipeline with minimal user intervention, SC segmentation and spatial normalization into a reference space was implemented in order to assess quantitative morphological and structural parameters (cross-sectional areas, scalar DTI and MT/ihMT metrics) in specific white and gray matter regions of interest. The multi-parametric MRI metrics collected allowed upper and lower cervical levels to be distinguished, with higher ihMT ratio (ihMTR), higher axial diffusivity (λ∥ ) and lower radial diffusivity (λ⊥ ) at C2 compared with C5. Significant differences were also observed between white matter fascicles, with higher ihMTR and lower λ∥ in motor tracts compared with posterior sensory tracts. Finally, aging was found to be associated with significant metric alterations (decreased ihMTR and λ∥ ). The methodology proposed here, which can be easily transferred to the clinic, provides new insights for SC characterization. It bears great potential to study focal and diffuse SC damage in neurodegenerative and demyelinating diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Minimizing the effects of magnetization transfer asymmetry on inhomogeneous magnetization transfer (ihMT) at ultra-high magnetic field (11.75 T).

OBJECTIVES: The recently reported inhomogeneous magnetization transfer technique (ihMT) has been proposed for specific imaging of inhomogeneously broadened lines, and has shown great promise for characterizing myelinated tissues. The ihMT contrast is obtained by subtracting magnetization transfer images obtained with simultaneous saturation at positive and negative frequency offsets (dual frequency saturation experiment, MT (+/-)) from those obtained with single frequency saturation (MT (+)) at the same total power. Hence, ihMT may be biased by MT-asymmetry, especially at ultra-high magnetic field. Use of the average of single positive and negative frequency offset saturation MT images, i.e., (MT (+)+MT (-)) has been proposed to correct the ihMT signal from MT-asymmetry signal. MATERIALS AND METHODS: The efficiency of this correction method was experimentally assessed in this study, performed at 11.75 T on mice. Quantitative corrected ihMT and MT-asymmetry ratios (ihMTR and MTRasym) were measured in mouse brain structures for several MT-asymmetry magnitudes and different saturation parameter sets. RESULTS: Our results indicated a "safe" range of magnitudes (/MTRasym/<4 %) for which MT-asymmetry signal did not bias the corrected ihMT signal. Moreover, experimental evidence of the different natures of both MT-asymmetry and inhomogeneous MT contrasts were provided. In particular, non-zero ihMT ratios were obtained at zero MTRasym values. CONCLUSION: MTRasym is not a confounding factor for ihMT quantification, even at ultra-high field, as long as MTRasym is restricted to ±4 %.

Magnetization transfer from inhomogeneously broadened lines (ihMT): Experimental optimization of saturation parameters for human brain imaging at 1.5 Tesla.

PURPOSE: Recently a new MR endogenous contrast mechanism was reported. It allows specifically imaging the magnetization transfer (MT) effect arising from inhomogeneously broadened components of the NMR spectrum, and was hence dubbed ihMT. Such unique NMR lineshape properties are presumably occurring in myelin because of its specifically ordered, multilayered sheath structure. Here, optimization of a pulsed ihMT preparation module is presented to provide guidance for future studies and improve the understanding of underlying contrast mechanisms. METHODS: This study was performed at 1.5 Tesla on healthy volunteers. A pulsed ihMT preparation was implemented in combination with a HASTE readout module. The pulse width, interpulse repetition time, total saturation duration and RF saturation power were considered for optimization of the ihMT sensitivity and contrast. RESULTS: An optimal configuration of the preparation module was derived, leading to 10% ihMT signal in internal capsule (relative to unsaturated data) and around 200% signal increase relative to gray matter, i.e., approximately 10-fold superior contrast compared with conventional MT ratios, measured under similar experimental conditions. CONCLUSION: Overall the ihMT sequence was robust, sensitive and very specific for white matter. These findings suggest great potential for assessing brain myelination and for better characterization of myelin related disorders.

Fast imaging strategies for mouse kidney perfusion measurement with pseudocontinuous arterial spin labeling (pCASL) at ultra high magnetic field (11.75 tesla).

BACKGROUND: To derive an adapted protocol at ultra high magnetic field for mouse kidney perfusion measurements using pCASL in combination with three widely available fast imaging readouts: segmented SE EPI (sSE EPI), RARE, and TrueFISP. METHODS: pCASL sSE EPI, pCASL RARE, and pCASL TrueFISP were used for the acquisition of mouse kidney perfusion images in the axial and coronal planes at 11.75T. Results were compared in terms of perfusion sensitivity, signal-to-noise ratio (SNR), blood flow values, intrasession and intersession repeatability, and image quality (subjectively classified into three grades: good, satisfactory, and unacceptable). RESULTS: Renal cortex perfusion measurements were performed within 2 min with pCASL RARE/pCASL TrueFISP and 4 min with pCASL sSE EPI. In an axial direction, SNR values of 6.6/5.6/2.8, perfusion sensitivity values of 16.1 ± 3.7/13.6 ± 2.4/13.4 ± 1.0 %, blood flow values of 679 ± 149/466 ± 111/572 ± 46 mL/100 g/min and in-ROI variations values of 192/161/181 mL/100 g/min were obtained with pCASL sSE EPI/pCASL RARE/pCASL TrueFISP. Highest SNR per unit of time (1.8) and highest intra/intersession reliability (92.9% and 95.1%) were obtained with pCASL RARE, which additionally presented highly reproducible satisfactory image quality. In coronal plane, significantly lower SNR, perfusion sensitivity and perfusion values were obtained for all techniques compared with that in the axial plane (P < 0.05) due to magnetization saturation effects. CONCLUSION: pCASL RARE demonstrated more advantages for longitudinal preclinical kidney perfusion studies at ultra high magnetic field.

In vivo MR imaging of the human skin at subnanoliter resolution using a superconducting surface coil at 1.5 Tesla.

PURPOSE: To demonstrate the feasibility of a highly sensitive superconducting surface coil for microscopic MRI of the human skin in vivo in a clinical 1.5 Tesla (T) scanner. MATERIALS AND METHODS: A 12.4-mm high-temperature superconducting coil was used at 1.5T for phantom and in vivo skin imaging. Images were inspected to identify fine anatomical skin structures. Signal-to-noise ratio (SNR) improvement by the high-temperature superconducting (HTS) coil, as compared to a commercial MR microscopy coil was quantified from phantom imaging; the gain over a geometrically identical coil made from copper (cooled or not) was theoretically deduced. Noise sources were identified to evaluate the potential of HTS coils for future studies. RESULTS: In vivo skin images with isotropic 80 µm resolution were demonstrated revealing fine anatomical structures. The HTS coil improved SNR by a factor 32 over the reference coil in a nonloading phantom. For calf imaging, SNR gains of 380% and 30% can be expected over an identical copper coil at room temperature and 77 K, respectively. CONCLUSION: The high sensitivity of HTS coils allows for microscopic imaging of the skin at 1.5T and could serve as a tool for dermatology in a clinical setting.

High-resolution mouse kidney perfusion imaging by pseudo-continuous arterial spin labeling at 11.75T.

PURPOSE: Quantitative measure of blood flow provides important information regarding renal function, nephropathies and viability of kidney transplantation. Therefore, a method that would allow quantitative and reliable assessment of the renal microvascular perfusion would be very valuable. Arterial spin labeling Magnetic Resonance Imaging has started to be widely used for human studies. For rodents though, despite the increasing number of transgenic mouse models, renal perfusion Magnetic Resonance Imaging has been only sparsely reported. This study investigated the use of FAIR (flow-sensitive alternating inversion recovery) and pseudo-continuous arterial spin labeling (pCASL) for mouse renal blood flow measurements. METHODS: FAIR and pCASL were compared in terms of sensitivity, absolute quantification, reproducibility and flexibility of implementation. Multislice and coronal imaging were also investigated. Studies were performed at 11.75 T with volumic transmitter/receiver radiofrequency coils and fast imaging. RESULTS: pCASL demonstrated better experimental flexibility and higher sensitivity compared to FAIR (> +20%). Renal blood flow values in the range of 550-750 mL/100 g/min for the cortex and of 140-230 mL/100 g/min for the medulla, consistent with literature data, were measured. CONCLUSION: pCASL was successfully applied at very high field for mouse renal blood flow measurements, demonstrating high sensitivity, flexibility and multislice imaging capability. pCASL may be considered as a method of choice for mouse kidney perfusion studies.

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma.

Antiangiogenic therapy can produce transient tumor regression in glioblastoma (GBM), but no prolongation in patient survival has been achieved. We have constructed a nanosystem targeted to tumor vasculature that incorporates three elements: (i) a tumor-homing peptide that specifically delivers its payload to the mitochondria of tumor endothelial cells and tumor cells, (ii) conjugation of this homing peptide with a proapoptotic peptide that acts on mitochondria, and (iii) multivalent presentation on iron oxide nanoparticles, which enhances the proapoptotic activity. The iron oxide component of the nanoparticles enabled imaging of GBM tumors in mice. Systemic treatment of GBM-bearing mice with the nanoparticles eradicated most tumors in one GBM mouse model and significantly delayed tumor development in another. Coinjecting the nanoparticles with a tumor-penetrating peptide further enhanced the therapeutic effect. Both models used have proven completely resistant to other therapies, suggesting clinical potential of our nanosystem.